Alzheimer?s-focused Administrative Supplement to Enhance the Imaging Genomics of the Aging Brain Project Project Summary/Abstract We request an administrative supplement for our ?Imaging Genomics of the Aging Brain? study (R01 AG058464). The goal of this administrative supplement is to extend our existing study to include a focus on Alzheimer?s disease and related dementias (ADRD). Currently our NIA funded project is designed to characterize the genetic influences on normal aging-related changes in neuroanatomic, neurophysiologic and neurocognitive indices in randomly selected Mexican American pedigrees. This supplement will support additional work, planned and performed by original and new project investigators, to advance the primary goal of our study: elucidating the genetic architecture underlying normal and pathologic brain aging. Our requested administrative supplement is in response to NOT-AG-20-008, as we integrate ADRD specific procedures and biomarkers into a project previously focused more on normal brain aging. In our currently funded project, we are re-phenotyping the oldest 700 Mexican American individuals ~10 years after their initial assessment as part of a pedigree-based, mixed longitudinal design. While our current study takes advantage of more powerful methods for the detection of genetic and environmental influences of healthy aging in longitudinal data, it does not include a formal assessment of Alzheimer?s disease or related dementias, nor are biomarkers associated with Alzheimer?s disease indexed. Thus, as part of this supplement, we aim to (1) integrate a culturally appropriate diagnostic screening into our existing protocol, (2) index ADRD related blood-based biomarkers using ultrasensitive methods for the quantitation of low abundance proteins (SIMOA technology), and (3) for each biomarker estimate the effect size on ARDR risk, the heritability, and the extent to which the biomarkers and ADRD share genetic factors. To achieve these aims, we partnered with Drs. Sudha Seshadri and Gladys Maestre, both world renowned experts in Alzheimer?s disease who will directly oversee our diagnostic aim. Although we will expand our brain aging genomics project to include diagnostic procedures and measure Alzheimer?s disease related biomarkers, the work proposed in this administrative supplement is within the scope of our originally supported research given the prevalence rates for dementia among individuals 70 years of age or older. Given the dearth of Alzheimer?s research involving the Mexican American community and evidence that this under-represented group is at increased risk for Alzheimer?s disease and related dementias, our supplement has the potential to help minimize this growing health disparity. This administrative supplement will provide pilot data for large-scale ADRD research projects in this underserved population. Dr. David Glahn, Boston Children?s Hospital, and Dr. John Blangero, University of Texas Rio Grande Valley School of Medicine, are co-principal investigators on this application. Our administrative supplement is in response to NOT-AG-20-008, as we integrate Alzheimer?s specific procedures and biomarkers into a project focused on normal brain aging.